Cardiovascular calcification in hemodialysis patients: A Qatar-based prevalence and risk factors study

Background: Patients with end-stage kidney disease on hemodialysis (HD) have an increased risk of death due to the high prevalence of cardiovascular disease. Vascular calcification (VC) is predictive of cardiovascular disease and mortality. We conducted a study to evaluate the prevalence and risk factors for VC in dialysis patients in Qatar. Methods: This is a retrospective nationwide study including all chronic ambulatory dialysis patients in Qatar from 2020 to 2022. We used our national electronic medical record to track demographics, clinical characteristics, comorbidities, laboratory values, and diagnostic data for each patient. Calcifications were assessed by echocardiography (routinely done for all our dialysis population per national protocol), computed tomography, X-ray, and ultrasound. The study protocol was approved by the local medical research ethics committee (MRC-01-20-377). Results: 842 HD patients were included in this study. Vascular calcifications (VC) were prevalent in 52.6% of patients. The main site of VC was Mitral valve calcifications in 55.5% of patients. Patients with VC were significantly older and had more prevalence of diabetes mellitus (p = 0.001 and p = 0.006, respectively). There was no statistically significant difference between patients with calcifications and patients without calcifications regarding serum calcium, phosphorus, and PTH level. In multivariate analysis, age and diabetes significantly increased the risk factor for calcification (95% CI 1.033–1.065, p < 0.0001, and 95% CI 1.128–2.272, p < 0001, respectively). Moreover, higher vitamin D levels and higher doses of IV Alfacalcidol were significant risk factors for calcifications (95% CI 1.005–1.030, p < 0.007, and 95% CI 1.092–1.270, p < 0.0001, respectively). Conclusion: Our study found that vascular calcification was widespread among our dialysis population in Qatar. Implementing the practice of echocardiography in dialysis patients was extremely helpful and the most productive in detecting vascular calcification. Diabetes mellitus almost doubles the risk for vascular calcifications in dialysis patients. These results are beneficial in identifying risk factors for vascular calcification, which can help stratify dialysis patients’ risk of cardiovascular disease and optimize prevention efforts.

Aortic arterial calcification (AAC) increases with age 8 and has been associated with an increased risk of cardiovascular incidents. 9,10The presence of arterial calcification is predictive of CVD and mortality. 10AAC is an independent predictor of obstructive coronary disease and correlates with coronary artery calcification (CAC). 11Up to 80-90% prevalence of vascular calcification in ESRD patients has been reported. 12Coronary calcification is associated with CVD, myocardial infarction, and all-cause mortality in the CKD population, including patients on dialysis. 13Bone mineral metabolism is tightly regulated by a delicate balance between parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), vitamin D, and other factors.In ESRD patients, disturbances in this equilibrium occur due to impaired renal excretion of phosphate and reduced vitamin D activation, leading to secondary hyperparathyroidism, elevated serum phosphate levels, and abnormal FGF23 concentrations. 14These derangements in mineral metabolism have been linked to the development and progression of vascular calcification in ESRD patients. 15Hemodialysis (HD), a cornerstone therapy for ESRD, often further exacerbates the risk of vascular calcification through mechanisms that involve alterations in bone mineral metabolism. 16his intricate interplay between bone and vasculature has gained increasing recognition in recent years, with research focusing on elucidating the underlying pathophysiological mechanisms, assessing its consequences on patients' health, and exploring the best modalities in monitoring and treatment. 17mad Medical corporation (HMC), a network of government hospitals, is the sole provider of Hemodialysis (HD).Our healthcare system consists of inpatient and ambulatory dialysis services.All ambulatory dialysis units under Hamad General Hospital were included in this study (4 dialysis facilities: Fahad Bin Jassim Kidney Center, Al Shamal, Al Shahaniya, and Al Wakra units).Details of our service have been explained in multiple publications. 18,19Dialysis populations are rising in the State of Qatar and are predicted to rise 5% annually till 2030.Projections indicate that the number of dialysis patients being cared for at any given time will surpass 1600 by that year. 20d 95% CI 1.128-2.272,p < 0001, respectively).Moreover, higher vitamin D levels and higher doses of IV Alfacalcidol were significant risk factors for calcifications (95% CI 1.005-1.030,p < 0.007, and 95% CI 1.092-1.270,p < 0.0001, respectively).Conclusion: Our study found that vascular calcification was widespread among our dialysis population in Qatar.Implementing the practice of echocardiography in dialysis patients was extremely helpful and the most productive in detecting vascular calcification.Diabetes mellitus almost doubles the risk for vascular calcifications in dialysis patients.These results are beneficial in identifying risk factors for vascular calcification, which can help stratify dialysis patients' risk of cardiovascular disease and optimize prevention efforts.

BACKGROUND
End-stage kidney disease (ESRD) is a prevalent and debilitating condition affecting millions of individuals worldwide, characterized by a near-total loss of renal function.Among the numerous complications associated with ESRD, vascular calcification has emerged as a significant concern due to its association with cardiovascular disease (CVD) morbidity and mortality. 1Vascular calcification involves the pathological deposition of calcium phosphate crystals within the walls of arteries and veins, leading to vessel stiffness, decreased compliance, and an increased risk of adverse cardiovascular events such as myocardial infarction and stroke. 2 Vascular calcification is highly prevalent in ESRD patients and occurs decades earlier than in the general population, 3 and its progression accelerates dramatically once a patient initiates chronic dialysis. 4This is of great clinical significance, as the presence and degree of calcification independently predict future cardiovascular events, as well as mortality. 5,6lcification can occur in both the intimal and medial layers of the vasculature, but medial calcification is considered the more common and significant form of calcification in ESRD. 7ardiovascular calcification in hemodialysis patients: A Qatar-based prevalence and risk factors study The objective of this study is to evaluate the possible relationship between vascular calcification and bone mineral metabolism in patients on hemodialysis.

METHODS
This is a retrospective nationwide study conducted in the ambulatory dialysis units in Qatar from 2020 to 2022.

Inclusion Criteria
We included patients with end-stage kidney disease receiving chronic hemodialysis treatment in the period between January 2020 and December 2022.The patient should be on continuous hemodialysis for more than 3 months.The patient should have regular biochemical laboratory tests for mineral and bone disorder (MBD) done per unit protocol.

Exclusion Criteria
We excluded pregnant female patients, patients lacked blood tests related to MBD, and children (under the age of 14 years).

Study Procedure and Data Collection
We utilized our electronic medical record system to monitor and record various patient-related information, such as demographics, clinical characteristics, comorbidities, laboratory values, and diagnostic data.The foundational demographic data encompassed age and gender, while comorbidities were assessed in terms of the presence of conditions such as diabetes mellitus, hypertension, cardiovascular disease, cerebrovascular disease, obstructive lung disease, chronic liver disease, and malignancy.Laboratory investigations included parathyroid hormones (PTH), serum-corrected calcium, and phosphorus, and vitamin D levels were recorded for all patients in the study.
Moreover, all data for medications used for bone and mineral disorder were also collected (calcium carbonate, Sevelamer carbonate, Intravenous Alfacalcidol, Cinacalcet and Intravenous Etelcalcetide) and the average medication doses per week were calculated.Vascular calcifications were assessed by echocardiography (which is routinely done for all our dialysis population per local protocol).Other radiology studies (that were done for other indications during the study period) were used to detect vascular calcification too.Investigations used included abdominal X-ray, chest X-ray, abdominal and pelvis computed tomography (CT), abdominal and extremities ultrasound, neck ultrasound (US) Doppler, and others.The severity of vascular calcification was reported if it was included in the radiology report.

Statistical Analysis
Statistical analysis was performed using Statistical Package for Social Sciences version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).Normally distributed data were expressed as mean ± standard deviation or median and range, while categorical variables were expressed as absolute and relevant frequencies.For comparison between groups, a paired t-test was used for normally distributed variables, while a chi-square test was used for ordinal distributed variables.P < 0.05 (two-tailed) was considered statistically significant.Multivariate regression analysis was done to assess the risk factors for vascular calcifications.

Ethical Approval
This study was approved by the Institutional Review Board (IRB), Medical Research Center of Hamad Medical Corporation (MRC-01-20-377).

1-Study Population and Demographics
842 HD patients fulfilled the inclusion criteria and were included in the study.The mean age was 59.8 ± 15.3 years, and 61.8% were male, while 38.2% were female.56.6% of the patients were native population while 43.4% were expatriates.The most common comorbidities were hypertension in 96.3% of patients, followed by diabetes in 69.2% of patients (Table 1).Cardiovascular calcification in hemodialysis patients: A Qatar-based prevalence and risk factors study without calcifications (p = 0.003 and p = 0.018, respectively) (Table 2).The weekly doses of calcium carbonate and Etelcalcetide showed no significant differences between the two groups (p = 0.758 and p = 0.327, respectively).However, there were significantly higher doses of cinacalcet and IV Alfacalcidol in patients with calcifications than in patients without calcifications (p = 0.021 and p = 0.003, respectively) (Table 2).

A-Univariate Analysis
Parameters with significant differences between patients with VC and no VC were further analyzed.
In univariate analysis, we found that all factors significantly different in the previous analysis carried a statistically significant risk for VC (DM, Age, Vitamin D level, Cinacalcet dose, and IV Alfacalcidol dose).The strongest risk was for DM with OR 2.65 (1.958-3.595,P = 0.000) (Table 3).

DISCUSSION
Vascular calcification poses a significant challenge among patients with end-stage kidney disease (ESRD), as it is intricately linked with unfavorable outcomes. 21 1 summarizes the demographic and general characteristics of the study population.

2-Comparison Between Patients with Vascular Calcification and Without Vascular Calcifications
Patients with vascular calcifications were significantly older (61.6y/o vs. 58 y/o p = 0.001) and were more likely to have diabetes mellitus compared to patients without vascular calcifications (75% vs. 28.6%p = 0.006).There was no statistically significant difference between patients with vascular calcifications and patients without it regarding serum calcium and PTH levels (p = 0.4 and p = 0.75, respectively).However, Patients with calcifications had significantly higher vitamin D levels and lower phosphorus levels than patients  to be intimal calcification) of hemodialysis patients using computed tomography and demonstrated that the degree of abdominal aortic calcification was significantly advanced in people with diabetes compared to non-diabetics.
2][33][34] Old age was associated with vascular calcification in both our study and its predecessors. 35,36n our study, we observed no association between the levels of calcium, phosphorus, and PTH and the occurrence of calcification.However, our findings notably revealed a significant correlation between elevated vitamin D levels and vascular calcification (Tables 2 and 3).Our findings are similar to those of another study by Rosa-Diez et al., 37 while London et al. observed that in adult hemodialysis patients, 1,25D and 25D levels were negatively correlated with aortic stiffness but not with vascular calcification. 38ur study stands out for being the inaugural investigation into the dialysis population in Qatar to explore vascular calcifications in this high-risk population.Conducted on a nationwide scale, our study utilized data sourced from the national electronic medical record, recognizing that while this method ensures a comprehensive dataset, the possibility of occasional missing data is acknowledged.Our practice mandates having an echocardiogram in all dialysis patients elevating the precision and thoroughness of vascular calcification identifications in this patient population.

Study Limitations
Our

Table 1 . Patient demographics and laboratory characteristics.
*All values are presented as means + standard deviation (SD).COPD, chronic obstructive pulmonary disease; PTH, parathyroid hormone.

Table 2 . Comparison between patients with and without calcifications.
22L. 2024 / ART.18Cardiovascular calcification in hemodialysis patients: A Qatar-based prevalence and risk factors study the region, delves into the prevalence of vascular calcifications in the hemodialysis population and scrutinizes potential risk factors through a comprehensive multivariate analysis.The Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD Working Group guidelines for CKD-MBD 201722propose that lateral abdominal radiograph can be used to detect the presence or *All values presented as means + standard deviation (SD).DM, Diabetes Mellitus; CVD, Cardiovascular disease; CVA, Cerebrovascular disease; COPD, Chronic obstructive pulmonary disease; CLD, Chronic liver disease.

Table 3 . Regression analysis: Risk factors for vascular calcifications in ESRD patients on hemodialysis.
Recognizing the significance of dialysis vintage as a variable, its absence underscores the need for cautious interpretation of our findings.Future studies incorporating this crucial parameter would provide a more nuanced understanding of the relationship between dialysis vintage and the risk of calcifications.While acknowledging the limitations of our study, we recommend implementing a standardized approach for detecting calcifications in all dialysis patients, ensuring uniformity in diagnostic methods.This could involve incorporating more comprehensive imaging techniques beyond echocardiogram, thereby enhancing the overall accuracy of vascular calcification assessments.Future research may benefit from prospective designs to further investigate and address the nuances associated with calcification detection in this patient population.CONCLUSIONSOur national study is the first to report a high prevalence of vascular calcifications in the dialysis population in Qatar.Implementing the mandatory practice of having echocardiography in dialysis patients was extremely helpful and productive in detecting vascular calcification.Diabetes mellitus almost doubles the risk of vascular calcifications in dialysis patients.Old age, higher vitamin D levels, and high doses of IV Alfacalcidol were significant risk factors for calcifications in dialysis patients.These results are beneficial in identifying risk factors for vascular calcification, which can help stratify dialysis patients' risk of cardiovascular disease and optimize prevention efforts.Considering these findings, we recommend implementing a standardized protocol for vascular calcification screening in dialysis patients, ensuring consistent and thorough assessments.Additionally, healthcare providers should be vigilant in monitoring and managing vascular calcification risk factors, with particular attention to diabetes mellitus, advanced age, and vitamin D levels.Further research is warranted to explore preventive interventions tailored to individuals at higher risk.